PROJECT SUMMARY Pancreatic cancer is the fourth most common cause of cancer related deaths in the United States with a 5-year survival rate less than 10%. Although it is characterized by a small number of well-defined genetic alterations, such as mutations of the KRAS oncogene as well as TP53, CDKN2A, and SMAD4 tumor suppressors, efforts to pharmacologically target those pathways have been unsuccessful. In contrast, the epigenetic networks that drive pancreatic cancer are poorly understood at the molecular level and unexplored as therapeutic targets. Epigenetic alterations undergo selective pressure, drive neoplastic progression, and result from mutations and copy number alterations in chromatin modifying enzymes. Considering that rewired epigenetic circuitries are not present in normal cells, yet essential in cancer, identification and targeting the responsible enzymes may uncover an Achilles? heel for the development of patient tailored therapies. Mutations in KDM6A, an X chromosome encoded histone demethylase, and KMT2C and KMT2D methyltransferases are frequent in pancreatic cancer and define a subgroup with distinct histology and dismal prognosis. KDM6A, KMT2C, and KMT2D are part of a COMPASS (COMplex of Proteins ASsociated with Set1)-like complex which mono-methylates histone H3K4 to delimit enhancer chromatin. Long stretches of enhancer chromatin form ?super-enhancers? which preferentially regulate genes that orchestrate cell fate and lineage commitment decisions. We found that mutations in the COMPASS complex rewire ?super-enhancers? to erase identity and favor the development of poorly differentiated and aggressive tumors. Furthermore, loss of KDM6A exhibits a gender specific tumor suppressor role in mice, with females developing distinct tumors of squamous and quasi-mesenchymal histology. High-throughput screening using a library of small molecule inhibitors revealed that COMPASS complex mutant pancreatic cancer is sensitive to Bromodomain and Extra-Terminal (BET) domain family of inhibitors, suggesting a therapeutic niche that can be exploited for personalized therapies. Here, we generated genetically engineered mice and human cell lines to conditionally delete Kdm6a, Kmt2c, and Kmt2d and propose to (a) comprehensively study the role of COMPASS complex in the initiation and progression of pancreatic cancer, (b) map the epigenetic changes that rewire enhancer chromatin to facilitate pancreatic oncogenesis, and (c) identify and target epigenetic vulnerabilities stemming from loss of COMPASS complex.